Optically active chroman and thiochroman derivatives

ABSTRACT

The present invention includes a compound having the following general formula (1):                    
     in which 
     x represents an oxygen atom or a sulfur atom, 
     m represents an integer of 2 to 14, and 
     n represents an integer of 2 to 7, 
     or hydrates or pharmaceutically acceptable salts thereof. The compound of general formula (1) is advantageous in pharmaceutical use because of its far superior anti-estrogenic activity over the corresponding racemic mixture.

This application is a 371 of PCT/JP00/08801 Dec. 13, 2000.

TECHNICAL FIELD

The present invention relates to optically active chroman or thiochromanderivatives having anti-estrogenic activity.

BACKGROUND ART

In treating diseases caused by abnormal tissue growth that is dependentupon a certain sexual steroidal hormone such as estrogen, it is highlyimportant to significantly inhibit, more preferably completelyeliminate, the effect induced by the hormone. For this purpose, it isdesirable to reduce the level of hormone capable of acting on thesteroidal hormone receptor site. For instance, anti-estrogenic agentsare commonly administered for alternative or combination therapy tolimit the production of estrogen to the amount less than required toactivate the receptor site. However, such conventional technique forblocking estrogen production could not sufficiently inhibit the effectinduced through the estrogen receptor. Practically, even when estrogenis completely absent, some of the receptors may be activated. It wastherefore considered that estrogen antagonists could provide bettertherapeutic effect in comparison to the technique for blocking only theproduction of sexual steroidal hormone. Thus, numerous estrogenantagonists have been developed. For example, many patent publicationsincluding U.S. Pat. Nos. 4,760,061, 4,732,912, 4,904,661, 5,395,842 andWO 96/22092 disclose various anti-estrogenic compounds. Sometimes,however, prior art antagonists may themselves act as agonists, andtherefore activate rather than block the receptor. For example,Tamoxifen has been most widely used as an anti-estrogenic agent.However, this agent has a disadvantage that it exhibits estrogenicactivity in some organs (see, M. Harper and A. Walpole, J. Reprod.Fertile., 1967, 13, 101).

As another non-steroidal anti-estrogenic compound, WO 93/10741 disclosesa benzopyran derivative having an aminoethoxyphenyl substituent(s)(Endorecherche), the typical compound of which is EM-343 having thefollowing structure:

Said compound also has the agonistic effect. It is therefore required todevelop an anti-estrogenic compound which is substantially or completelyfree of agonistic effect and which can effectively block the estrogenreceptor.

In addition, it has been known that 7α-substituted derivatives ofestradiol, for example, 7α-(CH₂)₁₀CONMeBu derivatives, are steroidalanti-estrogenic agents without agonistic effect (see, EP-A 0138504, U.S.Pat. No. 4,659,516). Further, an estradiol derivative having a7α-(CH₂)₉SOC₅H₆F₅ substituent has also been disclosed (see, Wakeling etal., Cancer Res., 1991, 51, 3867).

Non-steroidal anti-estrogenic agents without agonistic effect have beenfirst reported by Wakeling et al. in 1987 (see, A. Wakeling and Bowler,J. Endocrinol., 1987, 112, R7). Meanwhile, U.S. Pat. No. 4,904,661discloses phenol derivatives having anti-estrogenic activity. Thesephenol derivatives generally have a naphthalene scaffold and include,typically, the following compounds:

Some chroman and thiochroman derivatives have been reported asanti-estrogenic compounds having no agonistic effect (WO 98/25916).Although the existing anti-estrogenic compounds having no agonisticeffect show a substantial therapeutic effect when administered viaintravenous or subcutaneous injection, they show a highly reducedtherapeutic effect when administered orally, probably due to their lowbioavailability by oral route, etc. Therefore, for convenience's sake inthe case of administration, it is desired to develop anti-estrogeniccompounds which show a sufficient effect when administered orally and atthe same time have no agonistic effect.

DISCLOSURE OF THE INVENTION

The object of the present invention is to provide optically activechroman or thiochroman derivatives with asymmetric center(s), which havean excellent anti-estrogenic activity and are advantageous inpharmaceutical use.

The present inventors have researched anti-estrogenic activity ofcompounds having various structures. As a result, we have found thatoptically active chroman or thiochroman derivatives represented bygeneral formulae (1) to (4) could be more advantageous in pharmaceuticaluse because of, for example, their far superior anti-estrogenic activityover the corresponding diastereomer mixture. The present invention hasbeen accomplished on the basis of this finding.

Namely, the present invention provides a compound having the followinggeneral formula (1):

in which

x represents an oxygen atom or a sulfur atom,

m represents an integer of 2 to 14, and

n represents an integer of 2 to 7,

or the following general formula (2):

in which

x represents an oxygen atom or a sulfur atom,

m represents an integer of 2 to 14, and

n represents an integer of 2 to 7,

or the following general formula (3):

in which

x represents an oxygen atom or a sulfur atom,

m represents an integer of 2 to 14, and

n represents an integer of 2 to 7,

or the following general formula (4):

in which

x represents an oxygen atom or a sulfur atom,

m represents an integer of 2 to 14, and

n represents an integer of 2 to 7,

or hydrates thereof.

In addition, the present invention provides an optically single isomerof a compound having general formula (1) or (2) where the carbon whichis on the side chain bonded to the 4-position of the parent scaffold(i.e., chroman or thiochroman ring) and to which the carboxylic acid insaid side chain is bonded has R- or S-configuration, and mixturesthereof.

Further, the present invention provides a pharmaceutical compositioncomprising an optically active compound of general formula (1), (2), (3)or (4) as an active ingredient. Furthermore, the present inventionprovides an anti-estrogenic pharmaceutical composition comprising theabove compound as an active ingredient. The present invention alsoprovides a therapeutic agent for breast cancer comprising the abovecompound as an active ingredient.

In the definition of a compound having general formula (1), (2), (3) or(4), m may preferably be an integer of 6 to 10, particularly 8 or 9, andn may preferably be an integer of 2 to 7, particularly 3 or 4.

Compounds of general formula (1) or (2) have chiral carbons at positions3 and 4 of the parent scaffold (i.e., chroman or thiochroman ring) ineither the (3S,4S) or (3R,4R) configuration. Any of these compounds ispreferred per se. In particular, the compounds having R- orS-configuration at the carbon to which the carboxylic acid is bonded aremore preferable, wherein said carbon is the carbon on the side chainwhich is bonded to the 4-position of the parent scaffold. Also preferredare compounds of general formula (2), particularly those compounds inwhich X is a sulfur atom.

Another aspect of the present invention includes compounds of generalformula (1) or (2) in which X is an oxygen atom.

Among compounds of general formula (1) or (2), preferred are thosecompounds in which X is an oxygen atom or a sulfur atom; m is an integerof 8 or 9; and n is an integer of 3 or 4. In particular, the compoundhaving R- or S-configuration at the carbon to which the carboxylic acidis bonded are more preferable, wherein said carbon is the carbon on theside chain which is bonded to the 4-position of the parent scaffold.

As typical examples of these compounds, the following compounds can bementioned:

10-[(3R,4R)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-(2R)-2-(4,4,5,5,5-pentafluoropentyl)decanoicacid;

10-[(3R,4R)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-(2S)-2-(4,4,5,5,5-pentafluoropentyl)decanoicacid;

10-[(3S,4S)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-(2R)-2-(4,4,5,5,5-pentafluoropentyl)decanoicacid;

10-[(3S,4S)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-(2S)-2-(4,4,5,5,5-pentafluoropentyl)decanoicacid;

10-[(3R,4R)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)decanoicacid;

10-[(3S,4S)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)decanoicacid;

10-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-(2R)-2-(4,4,5,5,5-pentafluoropentyl)decanoicacid;

10-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-(2S)-2-(4,4,5,5,5-pentafluoropentyl)decanoicacid;

11-[(3R,4R)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-(2R)-2-(4,4,5,5,5-pentafluoropentyl)undecanoicacid;

11-[(3R,4R)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-(2S)-2-(4,4,5,5,5-pentafluoropentyl)undecanoicacid;

11-[(3S,4S)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-(2R)-2-(4,4,5,5,5-pentafluoropentyl)undecanoicacid;

11-[(3S,4S)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-(2S)-2-(4,4,5,5,5-pentafluoropentyl)undecanoicacid;

11-[(3R,4R)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)undecanoicacid;

11-[(3S,4S)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)undecanoicacid;

11-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-(2R)-2-(4,4,5,5,5-pentafluoropentyl)undecanoicacid; and

11-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-(2S)-2-(4,4,5,5,5-pentafluoropentyl)undecanoicacid.

The compounds of the present invention may be obtained as hydrates.

The compound of general formula (1), (2), (3) or (4) may be administeredas a pharmaceutical composition in any dosage form suitable for theintended route of administration, in combination with one or morepharmaceutically acceptable diluents, wetting agents, emulsifiers,dispersants, auxiliary agents, preservatives, buffers, binders,stabilizers and the like. The compound and composition may beadministered parenterally or orally.

The dose of the compound can be suitably determined according to thephysique, age and physical condition of a patient, severity of thedisease to be treated, elapsed time after onset of the disease, etc.Because the compound of the present invention is expected to show ahigher therapeutic effect than the corresponding diastereomer mixture,it may be used in a smaller amount to achieve the same level oftherapeutic effect. For example, it is generally used in an amount of0.1 to 500 mg/day when orally administered and in an amount of 1 to 1000mg/month when parenterally administered (by intravenous, intramuscular,or subcutaneous route) for adult patient.

BEST MODE FOR CARRYING OUT THE INVENTION

The compound of general formula (1) or (2) can be prepared according toany one of the following Reaction Schemes 1 to 10 (Processes 1 to 10).In these Reaction Schemes 1 to 10, compounds marked with an asterisk(*), for example, compound (I*) based on compound (I), are defined asfollows:

(a) compounds (III*), (IV*), (XIII*), (XIV*), (XIX*), (XX*), (XXII*),(XXIV*), (XXXI*) and (XXXIV*): each carbon atom marked with an asteriskin these chemical structures shown in the reaction schemes takes asingle configuration; and

(b) compounds marked with an asterisk other than those defined above in(a): these compounds are in an optically active form.

The compound of general formula (3) or (4) can be prepared according toany one of the following Reaction Schemes 1 to 10 (Processes 1 to 10),starting with racemate (I) (Reaction Schemes 1 and 6), racemate (XII)(Reaction Scheme 2), racemate (VII) (Reaction Scheme 3), racemate (XVII)(Reaction Schemes 4 and 5), XXV (Reaction Scheme 7), racemate (XXIX)(Reaction Schemes 8 and 9), or optically active compounds (XXXV*) and(XXXVI*) (Reaction Scheme 10).

In the above Reaction Scheme 1 (Process 1), X, m and n are as definedabove in general formulae (1) to (4); each of R₁₁, R₁₂ and R₁₃represents a protecting group; each of L₁ and L₂ represents a leavinggroup; and m₁ equals m−2.

In the above Reaction Scheme 2 (Process 2), X, m and n are as definedabove in general formulae (1) to (4); and R₁₁ represents a protectinggroup.

In the above Reaction Scheme 3 (Process 3), X, m and n are as definedabove in general formulae (1) to (4); each of R₁₁ and R₁₃ represents aprotecting group; and L₁ represents a leaving group.

In the Reaction Scheme 4 (Process 4), X, m and n are as defined above ingeneral formulae (1) to (4); each of R₁₁ and R₁₃ represents a protectinggroup; and m₃+3 equals m.

In the above Reaction Scheme 5 (Process 5), X, m and n are as definedabove in general formulae (1) to (4); each of R₁₁ and R₁₃ represents aprotecting group; and m₃+3 equals m.

The preparation of the compounds according to the present invention willbe illustrated below in more detail, in line with the above-mentionedreaction schemes.

[Process 1]

Racemate (I) is resolved using a chiral column, for example, onecommercially available from DAICEL under the trade name ofCHIRALPAK-OT(+), OP(+) or AD, or CHIRALCEL-OA, OB, OJ, OK, OC, OD, OF orOG, to give optically active compound (I*).

In the presence of a base (e.g., n-butyllithium, s-butyllithium, sodiumhydride), compound (I*) is reacted with alkyne (II) in an inert solvent(e.g., tetrahydrofuran, diethyl ether, dioxane, dichloromethane,chloroform, preferably tetrahydrofuran or dioxane) at a temperatureranging from −78° C. to the boiling point of the reaction mixture,preferably from −78° C. to room temperature, to give compound (III*).

In the presence of a Lewis acid such as zinc iodide, compound (III*) isreduced with sodium cyanoborohydride (NaBH₃CN) in an inert solvent(e.g., tetrahydrofuran, diethyl ether, dioxane, dichloromethane,dichloroethane or chloroform, preferably dichloroethane) at atemperature ranging from −78° C. to the boiling point of the reactionmixture, preferably from 0° C. to room temperature, to give compound(IV*).

Using a catalyst (e.g., palladium on activated carbon, palladiumhydroxide, platinum oxide), compound (IV*) is hydrogenated in an inertsolvent (e.g., methanol, ethanol, ethyl acetate, tetrahydrofuran,dioxane, preferably tetrahydrofuran, ethyl acetate) at a temperatureranging from room temperature to the boiling point of the reactionmixture, preferably at room temperature, to give compound (V*). Compound(V*) can be directly prepared from compound (III*) through hydrogenationusing a catalyst (e.g., palladium on activated carbon, palladiumhydroxide or platinum oxide) in an inert solvent (e.g., methanol,ethanol, ethyl acetate, tetrahydrofuran, dioxane, preferablytetrahydrofuran, ethyl acetate) at a temperature ranging from roomtemperature to the boiling point of the reaction mixture, preferably atroom temperature.

Compound (V*) is subjected to deprotection of the alcoholic hydroxylgroup in an inert solvent to give compound (VI*).

In the presence of a base (e.g., triethylamine or pyridine), compound(VI*) is treated with methanesulfonyl chloride or p-toluenesulfonylchloride in an inert solvent (e.g., tetrahydrofuran, dioxane,dichloromethane, dichloroethane or chloroform, preferablydichloromethane) at a temperature ranging from room temperature to theboiling point of the reaction mixture, preferably at room temperature,to convert (CH₂)_(m)OH in compound (VI*) into (CH₂)_(m)—O—SO₂CH₃ or(CH₂)_(m)—SO₂—C₆H₄-p-CH₃. The compound thus obtained is then treatedwith a metal halide (e.g., sodium iodide or potassium iodide) in aninert solvent (e.g., acetone, tetrahydrofuran, dioxane, dichloromethane,dichloroethane or chloroform, preferably acetone) at a temperatureranging from room temperature to the boiling point of the reactionmixture, preferably at the boiling point of the reaction mixture, togive compound (VII*).

In the presence of a base (e.g., sodium hydride, sodium hydroxide orpotassium t-butoxide), compound (VII*) is reacted with a malonic esterof formula (VIII) (e.g., diethyl malonate or dimethyl malonate) in aninert solvent (e.g., tetrahydrofuran, dioxane, dimethylformamide,dichloromethane, dichloroethane or chloroform, preferablytetrahydrofuran) at a temperature ranging from room temperature to theboiling point of the reaction mixture to give compound (IX*).

In the presence of a base (e.g., sodium hydride, sodium hydroxide orpotassium t-butoxide), compound (IX*) is reacted with an alkylatingagent of formula (X) in an inert solvent (e.g., tetrahydrofuran, diethylether, dioxane, dimethylformamide, dichloromethane, dichloroethane orchloroform, preferably tetrahydrofuran) at a temperature ranging fromroom temperature to the boiling point of the reaction mixture to givecompound (XI*).

Compound (XI*) is treated with sodium hydroxide or potassium hydroxidein a solvent (e.g., water, ethanol, methanol, a water/ethanol mixture ora water/methanol mixture) at a temperature ranging from room temperatureto the boiling point of the reaction mixture, preferably at the boilingpoint of the reaction mixture, to give compound (XII*).

In a solvent (e.g., dimethyl sulfoxide, dimethylformamide, benzene,toluene, xylene, dioxane or tetrahydrofuran) and, if necessary, in thepresence of an acid (e.g., hydrogen chloride, sulfuric acid orp-toluenesulfonic acid), compound (XII*) is heated to a temperatureranging from 50° C. to the boiling point of the reaction mixture to givecompound (XIII*).

Next, compound (XIII*) is subjected to deprotection of the phenolichydroxyl group to give compound (XIV*).

[Process 2]

Compound (XIV*) may also be synthesized from compound (XII*) in thefollowing manner. A procedure analogous to Process 1 is repeated untilcompound (XII*) is prepared.

Compound (XII*) is subjected to deprotection of the phenolic hydroxylgroup to give compound (XV*).

In a solvent (e.g., dimethyl sulfoxide, dimethylformamide, benzene,toluene, xylene, dioxane or tetrahydrofuran) and, if necessary, in thepresence of an acid (e.g., hydrogen chloride, sulfuric acid orp-toluenesulfonic acid), compound (XV*) is heated to a temperatureranging from 50° C. to the boiling point of the reaction mixture to givecompound (XIV*).

[Process 3]

Compound (XIV*) can also be prepared from compound (VII*) in thefollowing manner.

In the presence of a base (e.g., sodium hydride, sodium hydroxide orpotassium t-butoxide), compound (VII*) is reacted with compound (XVI) inan inert solvent (e.g., tetrahydrofuran, dioxane, dimethylformamide,dichloromethane, dichloroethane or chloroform, preferablytetrahydrofuran) at a temperature ranging from −78° C. to the boilingpoint of the reaction mixture to give compound (XI*).

Compound (XI*) is converted into compound (XIV*) as in Process 1 or 2.

[Process 4]

Compound (XIV*) may also be prepared in the following manner.

In the presence of a catalyst such asbenzylidene-bis(tricyclohexylphosphine)dichlororuthenium, compound(XVII*) is reacted with compound (XVIII) in a solvent (e.g., methylenechloride, chloroform, benzene, toluene, xylene, dioxane,tetrahydrofuran, dimethyl sulfoxide or dimethylformamide) at atemperature ranging from −78° C. to the boiling point of the reactionmixture, preferably at the boiling point of the reaction mixture, togive compound (XIX*).

Using a catalyst (e.g., palladium on activated carbon, palladiumhydroxide, platinum oxide or Wilkinson's catalyst), compound (XIX*) ishydrogenated in an inert solvent (e.g., methanol, ethanol, ethylacetate, tetrahydrofuran, dioxane, dichloromethane, dichloroethane,chloroform or benzene) at a temperature ranging from room temperature tothe boiling point of the reaction mixture, preferably at roomtemperature, to give compound (XX*).

Compound (XX*) is converted into compound (XIV*) as in Process 1 or 2where compound (XI*) is converted into compound (XIV*).

[Process 5]

Further, compound (XIV*) may also be prepared in the following manner.

In the presence of a catalyst such asbenzylidene-bis(tricyclohexylphosphine)dichlororuthenium, compound(XVII*) is reacted with compound (XXI) in a solvent (e.g., methylenechloride, chloroform, benzene, toluene, xylene, dioxane,tetrahydrofuran, dimethyl sulfoxide or dimethylformamide) at atemperature ranging from −78° C. to the boiling point of the reactionmixture, preferably at the boiling point of the reaction mixture, togive compound (XXII*).

Using a catalyst (e.g., palladium on activated carbon, palladiumhydroxide, platinum oxide or Wilkinson's catalyst), compound (XXII*) ishydrogenated in an inert solvent (e.g., methanol, ethanol, ethylacetate, tetrahydrofuran, dioxane, dichloromethane, dichloroethane orbenzene) at a temperature ranging from room temperature to the boilingpoint of the reaction mixture, preferably at room temperature, to givecompound (XXIII*).

Compound (XXIII*), which is identical with compound (XI*) in Process 1,is converted into compound (XIV*) as in Process 1 or 2 where compound(XI*) is converted into compound (XIV*).

Compound (XVII*) used in Processes 4 and 5 can be prepared by eitherProcess 6 or 7 shown below.

In the above Reaction Scheme 6 (Process 6), X is as defined above ingeneral formulae (1) to (4); and R₁₁ represents a protecting group.

In the above Reaction Scheme 7 (Process 7), X is as defined above ingeneral formulae (1) to (4); R₁₁ represents a protecting group; and L₃represents a leaving group.

[Process 6] Preparation of Compound (XVII*)-Part I

Compound (I*) is reduced with lithium aluminum hydride ordiisobutylaluminum hydride in an inert solvent (e.g., diethyl ether,benzene, toluene, xylene, dioxane or tetrahydrofuran) at a temperatureranging from −78° C. to the boiling point of the reaction mixture togive compound (XXIV*).

In the presence of a Lewis acid such as zinc iodide, compound (XXIV*) isreacted with allyltrimethylsilane in an inert solvent (e.g.,tetrahydrofuran, dioxane, dichloromethane, dichloroethane or chloroform,preferably dichloroethane) at a temperature ranging from −78° C. to theboiling point of the reaction mixture, preferably from 0° C. to roomtemperature, to give compound (XVII*).

[Process 7] Preparation of Compound (XVII)-Part II

In the presence of anhydrous TBAF and, if necessary, accompanied byaddition of HMPA, compound (XXV) is reacted with allyltrimethylsilane inan inert solvent (e.g., dimethylformamide, dimethyl sulfoxide,tetrahydrofuran, dioxane, dichloromethane, dichloroethane or chloroform)at a temperature ranging from −78° C. to the boiling point of thereaction mixture, preferably from 0° C. to room temperature, to givecompound (XXVI).

In the presence of a base (e.g., lithium hexamethyl-disilazide,n-butyllithium, s-butyllithium, sodium hydride), compound (XXVI) isreacted with an alkylating agent (CH₃—L₃) in an inert solvent (e.g.,tetrahydrofuran, ether, dioxane, dichloromethane, chloroform, preferablytetrahydrofuran or dioxane) at a temperature ranging from −78° C. to theboiling point of the reaction mixture, preferably from −78° C. to roomtemperature, to give compound (XXVII).

Compound (XXVII) is reduced with lithium aluminum hydride in an inertsolvent (e.g., tetrahydrofuran, dioxane or diethyl ether) at atemperature ranging from −78° C. to the boiling point of the reactionmixture to give compound (XXVIII).

Compound (XXVIII) is reacted with diethyl azodicarboxylate andtriphenylphosphine in an inert solvent (e.g., toluene, dioxane,dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, dichloromethane,dichloroethane or chloroform) at a temperature ranging from −78° C. tothe boiling point of the reaction mixture, preferably from 0° C. to roomtemperature, to give compound (XVII).

Compound (XIV*) given by the above Processes 1 to 5 may also beconverted into a salt form because it has a carboxyl group.Pharmaceutically acceptable salts include, but are not limited to,sodium, potassium, calcium and magnesium salts. For example, a salt ofcompound (XIV*) can be prepared as follows.

Sodium methoxide is added to compound (XIV*) dissolved in an organicsolvent (e.g., dry methanol) at an appropriate temperature, for example,at room temperature, and the resulting mixture is stirred for about 30minutes to about 3 hours at the same temperature. After addition of anorganic solvent such as dry diethyl ether, the reaction mixture isevaporated under reduced pressure to remove the solvent, therebyobtaining a salt of the compound.

The compound of the present invention exists as various enantiomersbecause it contains three asymmetric carbon atoms. To obtain a singlestereoisomer, there are two techniques, one of which uses a chiralcolumn to resolve a mixture of stereoisomers and the other involvesasymmetric synthesis. The chiral column technique may be carried outusing a column commercially available from DAICEL under the trade nameof CHIRALPAK-OT(+), OP(+) or AD, or CHIRALCEL-OA, OB, OJ, OK, OC, OD, OFor OG, for example. Regarding asymmetric synthesis, the following willillustrate the asymmetric synthesis of the inventive compound withrespect to an asymmetric carbon atom, to which a side chain carboxylgroup is attached.

[Process 8]

In the presence of a catalyst such asbenzylidene-bis(tricyclohexylphosphine)dichlororuthenium, compound(XXIX*) is reacted with compound (XXX*) in a solvent (e.g., methylenechloride, chloroform, benzene, toluene, xylene, dioxane,tetrahydrofuran, dimethyl sulfoxide or dimethylformamide) at atemperature ranging from −78° C. to the boiling point of the reactionmixture, preferably at the boiling point of the reaction mixture, togive compound (XXXI*).

Compound (XXXI*) is then subjected to the following reactions in theorder stated, (a) reduction, deprotection and hydrolysis or (b)reduction, hydrolysis and deprotection, to give compound (XXXII*).

(a) Reduction, Deprotection and Hydrolysis

1) Reduction

In the presence of a catalyst (e.g., palladium on activated carbon,palladium hydroxide, platinum oxide or Wilkinson's catalyst), compound(XXXI*) is hydrogenated in an inert solvent (e.g., methanol, ethanol,ethyl acetate, tetrahydrofuran, dioxane or benzene) at a temperatureranging from 0° C. to the boiling point of the reaction mixture,preferably at room temperature, to give a reduction product.

2) Deprotection

Next, deprotection of the phenolic hydroxyl group is carried out to givea deprotected product.

3) Hydrolysis

By way of example, if R* is a group of formula (XXXVIII*), thedeprotected product is further treated with lithium hydroxide, sodiumhydroxide, lithium hydroxide plus hydrogen peroxide, sodium hydroxideplus hydrogen peroxide, or tetrabutylammonium hydroxide plus hydrogenperoxide in a solvent (e.g., a tetrahydrofuran/water mixture, a diethylether/water mixture, a dioxane/water mixture, a methanol/water mixture,an ethanol/water mixture) at a temperature ranging from room temperatureto the boiling point of the reaction mixture, preferably at roomtemperature, to give compound (XXXII*).

(b) Reduction, Hydrolysis and Deprotection

1) Reduction

In the presence of a catalyst (e.g., palladium on activated carbon,palladium hydroxide, platinum oxide or Wilkinson's catalyst), compound(XXXI*) is hydrogenated in an inert solvent (e.g., methanol, ethanol,ethyl acetate, tetrahydrofuran, dioxane or benzene) at a temperatureranging from 0° C. to the boiling point of the reaction mixture,preferably at room temperature, to give a reduction product.

2) Hydrolysis

By way of example, if R* is a group of formula (XXXVIII*), the reductionproduct is further treated with lithium hydroxide, sodium hydroxide,lithium hydroxide plus hydrogen peroxide, sodium hydroxide plus hydrogenperoxide, or tetrabutylammonium hydroxide plus hydrogen peroxide in asolvent (e.g., a tetrahydrofuran/water mixture, a diethyl ether/watermixture, a dioxane/water mixture, a methanol/water mixture, anethanol/water mixture) at a temperature ranging from room temperature tothe boiling point of the reaction mixture, preferably at roomtemperature, to give a carboxylic acid.

3) Deprotection

Next, deprotection of the phenolic hydroxyl group is carried out to givecompound (XXXII*).

[Process 9]

In the presence of a catalyst such asbenzylidene-bis(tricyclohexylphosphine)dichlororuthenium, compound(XXIX*) is reacted with compound (XXXIII*) in a solvent (e.g., methylenechloride, chloroform, benzene, toluene, xylene, dioxane,tetrahydrofuran, dimethyl sulfoxide or dimethylformamide) at atemperature ranging from −78° C. to the boiling point of the reactionmixture, preferably at the boiling point of the reaction mixture, togive compound (XXXIV*).

In the presence of a catalyst (e.g., palladium on activated carbon,palladium hydroxide, platinum oxide or Wilkinson's catalyst), compound(XXXIV*) is hydrogenated in an inert solvent (e.g., methanol, ethanol,ethyl acetate, tetrahydrofuran, dioxane or benzene) at a temperatureranging from 0° C. to the boiling point of the reaction mixture,preferably at room temperature, to give a reduction product.

Next, deprotection of the phenolic hydroxyl group is carried out to givecompound (XXXII*).

The chiral olefins of formulae (XXX*) and (XXXIII*) used in the aboveProcesses 8 and 9, respectively, may be synthesized as follows (ReactionScheme 10).

In the above Reaction Schemes 8, 9 and 10 (Processes 8, 9 and 10), X, mand n are as defined above in general formula (1); R* represents achiral auxiliary group; P represents a leaving group; L represents aleaving group; and m₂ and m₃ are integers that satisfy the relationm=m₂+m₃+2. The symbol R in formula (XXXIV*) represents an alkyl group.

Synthesis of Chiral Olefins

In the presence of a base (e.g., lithium diisopropylamide, lithiumhexamethyl-disilazide, sodium hexamethyl-disilazide, butyllithium) andHMPA, compound (XXXV*) is reacted with C₂F₅(CH₂)_(n)—L in an inertsolvent (e.g., tetrahydrofuran, toluene, diethyl ether, hexane,preferably tetrahydrofuran) at a temperature ranging from −78° C. to theboiling point of the reaction mixture, preferably from −30° C. to roomtemperature, to give compound (XXX*).

Alternatively, in the presence of a base (e.g., lithiumdiisopropylamide, lithium hexamethyl-disilazide, sodiumhexamethyl-disilazide, butyllithium) and HMPA, compound (XXXVI*) isreacted with compound (XXXVII) in an inert solvent (e.g.,tetrahydrofuran, toluene, diethyl ether, hexane, preferablytetrahydrofuran) at a temperature ranging from −78° C. to the boilingpoint of the reaction mixture, preferably from −30° C. to roomtemperature, to give compound (XXX*).

In the presence of a nucleophilic reagent (e.g., lithium hydroxide plushydrogen peroxide, lithium hydroxide, sodium methoxide, sodiumthioethoxide) or an acid (e.g., hydrochloric acid, sulfuric acid),compound (XXX*) is hydrolyzed in an inert solvent (e.g., methanol,ethanol, tetrahydrofuran, water, preferably a tetrahydrofuran/watermixture) at a temperature ranging from −78° C. to the boiling point ofthe reaction mixture, preferably from room temperature to 50° C., toconvert the chiral auxiliary group thereby giving compound (XXXIII*).

EXAMPLES

The present invention is more specifically explained by the followingexamples. However, it should be understood that the present invention isnot limited to these examples in any manner. In order to explain theeffectiveness of the compounds according to the present invention,typical compounds were tested for their anti-estrogenic activity in thetest example shown below. Table 1 shows chemical structures of thecompounds prepared in the examples.

TABLE 1

Example No. Formula X m n 2 (2) S 8 3 3 (1) S 8 3 4 (2) S 9 3 5 (1) S 93 7 (1) or (2) O 9 3 8 (1) or (2) O 9 3 10, Peak 1 (2) S 8 3 10, Peak 2(2) S 8 3 11, Peak 1 (1) S 8 3 11, Peak 2 (1) S 8 3

Example 1 Optical Resolution of7-Methoxy-3-(4-methoxyphenyl)-3-methylthiochroman-4-one

Optical resolution of7-methoxy-3-(4-methoxyphenyl)-3-methylthiochroman-4-one was carried outusing a chiral column (CHIRALCEL OD) to give(3R)-7-methoxy-3-(4-methoxyphenyl)-3-methylthiochroman-4-one and(3S)-7-methoxy-3-(4-methoxyphenyl)-3-methylthiochroman-4-one.

Example 2 Synthesis of10-[(3R,4R)-7-Hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)decanoicAcid

A solution of the(3S)-7-methoxy-3-(4-methoxyphenyl)-3-methylthiochroman-4-one prepared inExample 1 (15 g, 0.048 mol) in anhydrous tetrahydrofuran (250 ml) wascooled to −78° C. To this solution, lithium aluminum hydride (905 mg,0.024 mol) was added dropwise and the resulting mixture was stirred for12 hours at room temperature. After the reaction was completed,saturated aqueous ammonium chloride was added to the reaction mixture,which was then extracted three times with ethyl acetate. The combinedorganic layers were washed with water and saturated aqueous sodiumchloride, and then dried over anhydrous magnesium sulfate. Afterdistilling off the solvent, zinc iodide (18.0 g, 0.053 mol) andallyltrimethylsilane (15 ml, 0.088 mol) were added dropwise to asolution of the residue in 1,2-dichloroethane (300 ml) while cooling at0° C., followed by stirring overnight at room temperature. After thereaction was completed, water was added to the reaction mixture, whichwas then extracted three times with dichloromethane. The combinedorganic layers were washed with water and saturated aqueous sodiumchloride, and then dried over anhydrous magnesium sulfate. Afterdistilling off the solvent, the residue was purified by silica gelcolumn chromatography (eluent: ethyl acetate/hexane=1/4) to give(3R,4R)-7-methoxy-3-(4-methoxyphenyl)-3-methyl-4-(2-propenyl)thiochroman(10.8 g, Yield 67%).

¹H-NMR (270 MHz, CDCl₃): δ 7.27 (d, 2H, J=7.2 Hz), 6.91-6.87 (m, 3H),6.71 (s, 1H), 6.55 (dd, 1H, J=8.9, 2.4 Hz), 5.65-5.48 (m, 1H), 4.85 (d,1H, J=9.8 Hz), 4.66 (d, 1H, J=17.0 Hz), 3.81 (s, 3H), 3.76 (s, 3H), 3.60(d, 1H, J=12.1 Hz), 2.98 (d, 1H, J=12.1 Hz), 2.91-2.88 (m, 1H),1.96-1.82 (m, 2H), 1.21 (t, 3H, J=7.2 Hz).

Ethyl 2-(4,4,5,5,5-pentafluoropentyl)-8-nonenoate was separatelyprepared from 1-iodo-4,4,5,5,5-pentafluoropentane, diethyl malonate and1-iodo-6-heptene. A solution of this compound (4.55 g, 13.21 mmol),(3R,4R)-7-methoxy-3-(4-methoxyphenyl)-3-methyl-4-(2-propenyl)thiochroman(2.5 g, 7.342 mmol) andbenzylidene-bis(tricyclohexylphosphine)dichlororuthenium (302 mg, 0.367mmol) in dichloromethane (60 ml) was heated under reflux for 6 hours.After the reaction was completed, the solvent was distilled off and theresulting residue was purified by silica gel column chromatography(eluent: ethyl acetate/hexane=1/30) to give ethyl10-[(3R,4R)-7-methoxy-3-(4-methoxyphenyl)-3-methylthiochroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)-8-decenoate(3.46 g, Yield 72%) as an oil.

¹H-NMR (270 MHz, CDCl₃): δ 7.34 (d, 2H), 6.95 (m, 3H), 6.75 (d, 1H),6.58 (m, 1H), 5.42˜4.61 (m, 2H), 4.20 (m, 3H), 3.82 (d, 6H), 3.65 (d,1H), 2.98 (m, 1H), 2.75 (bs, 1H), 2.32 (m, 2H), 2.12˜0.98 (m, 22H).

10% Pd/C (1.04 g) was added to a solution of the ethyl10-[(3R,4R)-7-methoxy-3-(4-methoxyphenyl)-3-methylthiochroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)-8-decenoate(3.46 g, 5.268 mmol) in tetrahydrofuran (60 ml) followed by stirring for23 hours at room temperature under a hydrogen stream. After the reactionmixture was filtered, the solvent was distilled off and the resultingresidue was purified by silica gel column chromatography (eluent: ethylacetate/hexane=1/10) to give ethyl10-[(3R,4R)-7-methoxy-3-(4-methoxyphenyl)-3-methylthiochroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)decanoate(3.23 g, Yield 93%) as an oil.

¹H-NMR (270 MHz, CDCl₃): δ 7.28 (d, 2H), 6.88 (m, 3H), 6.70 (m, 1H),6.61˜6.55 (dd, 1H), 4.10 (q, 2H), 3.77 (d, 6H), 3.62 (d, 1H), 2.98 (d,1H), 2.75 (bs, 1H), 2.31 (m, 1H), 2.11˜1.89 (m, 2H), 1.73˜0.98 (m, 26H).

A solution of ethyl10-[(3R,4R)-7-methoxy-3-(4-methoxyphenyl)-3-methylthiochroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)decanoate(3.23 g, 4.902 mmol) in dichloromethane (60 ml) was cooled to −78° C. Tothis solution, a solution of boron tribromide in dichloromethane (1M,39.22 ml, 39.22 mmol) was slowly added dropwise, and the resultingmixture was stirred for 1 hour. The reaction vessel was then transferredto an ice-bath and the reaction mixture was further stirred for 3 hours.After the reaction was completed, water was added to the reactionmixture, which was then extracted with dichloromethane. The organiclayer was dried over anhydrous magnesium sulfate. After distilling offthe solvent, the residue was purified by silica gel columnchromatography (eluent: ethyl acetate/n-hexane=1/20) to give ethyl10-[(3R,4R)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)decanoate(2.08 g, Yield 67%) as a foam.

¹H-NMR (270 MHz, CDCl₃): δ 7.22 (d, 2H), 6.80 (m, 3H), 6.68 (m, 1H),6.43 (d, 1H), 5.81 (d, 1H), 5.01 (d, 1H), 4.10 (q, 2H), 3.61 (d, 1H),2.96 (d, 1H), 2.68 (bs, 1H), 2.38 (m, 1H), 2.17˜1.91 (m, 2H), 1.67˜0.98(m, 26H).

Ethyl10-[(3R,4R)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)decanoate(2.08 g, 3.297 mmol) and sodium hydroxide (527 mg, 13.19 mmol) wereadded to an ethanol/water mixture (40/10 ml), followed by heating underreflux for 4 hours. The reaction mixture was acidified with 2Nhydrochloric acid and then extracted with ethyl acetate. The organiclayer was dried over anhydrous magnesium sulfate. After distilling offthe solvent, the residue was purified by silica gel columnchromatography (eluent: ethyl acetate/hexane/dichloromethane=1/4/1) togive10-[(3R,4R)-7-hydroxy-3-(4-hydroxyphenyl)-3-methythiochroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)decanoicacid (1.8 g, Yield 91%) as a foam.

¹H-NMR (270 MHz, CDCl₃): δ 7.22 (d, 2H), 6.82 (m, 3H), 6.64 (d, 1H),6.52 (dd, 1H), 3.59 (d, 1H), 2.95 (d, 1H), 2.65 (bs, 1H), 2.37 (m, 1H),2.12˜1.91 (m, 2H), 1.74˜1.42 (m, 6H), 1.32˜0.98 (m, 17H).

Example 3 Synthesis of10-[(3S,4S)-7-Hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)decanoicAcid

The (3R)-7-methoxy-3-(4-methoxyphenyl)-3-methylthiochroman-4-oneprepared in Example 1 (11.4 g, 36.26 mmol) was dissolved intetrahydrofuran (40 ml) and ethanol (20 ml). To this solution, sodiumborohydride (2.74 g, 72.51 mmol) was added at −78° C., and the resultingmixture was stirred for 15 hours at room temperature. After the reactionwas completed, dichloromethane, methanol and saturated aqueous sodiumchloride were added to the reaction mixture, which was then extractedunder heating conditions. The organic layer was dried over anhydrousmagnesium sulfate. After distilling off the solvent,allyltrimethylsilane (10.74 ml, 67.6 mmol) and zinc iodide (12.9 g,40.57 mmol) were added to a solution of the residue in dichloromethane(300 ml) followed by stirring for 15 hours at room temperature. Waterwas added to the reaction mixture, which was then extracted withdichloromethane. The organic layer was washed with saturated aqueousammonium chloride and dried over anhydrous magnesium sulfate, and theresulting residue was purified by silica gel column chromatography(eluent: ethyl acetate/hexane=1/90) to give(3S,4S)-7-methoxy-3-(4-methoxyphenyl)-3-methyl-4-(2-propenyl)thiochroman(7.2 g, Yield 58%) as an oil.

¹H-NMR (270 MHz, CDCl₃): δ 7.32 (d, 2H), 6.91 (m, 3H), 6.75 (d, 1H),6.57 (dd, 1H), 5.45 (m, 1H), 4.83 (d, 1H), 4.67 (d, 1H), 3.81 (d, 6H),3.65 (d, 1H), 3.02 (d, 1H), 2.87 (d, 1H), 1.9 (m, 2H), 1.31 (s, 3H).

Benzylidene-bis(tricyclohexylphosphine)-dichlororuthenium (1.2 g, 1.5mmol) was added to a solution of(3S,4S)-7-methoxy-3-(4-methoxyphenyl)-3-methyl-4-(2-propenyl)thiochroman(7.1 g, 20.85 mmol) and 1-acetoxy-6-heptene (7.32 ml, 41.7 mmol) indichloromethane (100 ml), followed by heating under reflux for 8 hours.The reaction mixture was concentrated under reduced pressure and theresulting residue was purified by silica gel column chromatography(eluent: ethyl acetate/hexane=1/20) to give the desired olefin. Pd/C(2.2 g) was added to a solution of this olefin in ethyl acetate (80 ml)followed by stirring for 20 hours under a hydrogen stream. The reactionmixture was filtered and concentrated under reduced pressure to give1-acetoxy-8-[(3S,4S)-7-methoxy-3-(4-methoxyphenyl)-3-methylthiochroman-4-yl]octane(7.31 g, Yield 77.8%).

¹H-NMR (270 MHz, CDCl₃): δ 7.28 (d, J=13.19 Hz, 2H), 6.91 (m, 3H), 6.72(s, 1H), 6.59 (dd, 1H), 4.00 (t, 2H), 3.80 (d, 6H), 3.64 (d, 1H), 2.99(d, 1H), 2.73 (d, 1H), 2.03 (s, 3H), 1.51 (m, 2H), 1.4-0.85 (m, 15H).

A solution of potassium hydroxide (4.35 g, 77.65 mmol) in water (50 ml)was added to a solution of1-acetoxy-8-[(3S,4S)-7-methoxy-3-(4-methoxyphenyl)-3-methylthiochroman-4-yl]octane(7.31 g, 15.53 ml) in ethanol (100 ml), and the resulting mixture washeated with stirring under reflux for 12 hours. After the reactionmixture was concentrated under reduced pressure, water was added to theresidue, which was then extracted with ethyl acetate. The organic layerwas dried over anhydrous magnesium sulfate and then evaporated to removethe solvent. The residue was dissolved in dichloromethane (100 ml), andtriethylamine (4.33 ml, 31.06 mmol) and methanesulfonyl chloride (1.8ml, 23.29 mmol) were added to the solution followed by stirring for 1hour and 30 minutes at 5° C. After the reaction was completed, water wasadded to the reaction mixture, which was then extracted withdichloromethane. The organic layer was dried over anhydrous magnesiumsulfate and then evaporated to remove the solvent. Sodium iodide (11.6g, 77.65 mmol) was added to a solution of the residue in acetone (200ml), followed by heating under reflux for 3 hours. After the reactionmixture was filtered and concentrated under reduced pressure, water wasadded to the residue, which was then extracted with ethyl acetate. Theorganic layer was dried over anhydrous magnesium sulfate and thenevaporated to remove the solvent. The residue was purified by silica gelcolumn chromatography (eluent: ethyl acetate/hexane=1/10) to give1-iodo-8-[(3S,4S)-7-methoxy-3-(4-methoxyphenyl)-3-methylthiochroman-4-yl]octane(4.0 g, 7.42 mmol). Sodium hydride (0.62 g, 15.58 mmol) was added to asolution of separately prepared dimethyl2-(4,4,5,5,5-pentafluoropentyl)malonate (4.33 g, 14.85 mmol) intetrahydrofuran (40 ml) followed by stirring for 30 minutes at 0° C. Asolution of1-iodo-8-[(3S,4S)-7-methoxy-3-(4-methoxyphenyl)-3-methylthiochroman-4-yl]octanein tetrahydrofuran (40 ml) was added to the resulting mixture followedby stirring for 24 hours at room temperature. Water was added to thereaction mixture, which was then extracted with ethyl acetate. After theorganic layer was dried over anhydrous magnesium sulfate, the solventwas distilled off and the resulting residue was purified by silica gelcolumn chromatography (eluent: ethyl acetate/hexane=1/30) to givedimethyl2-{8-[(3S,4S)-7-methoxy-3-(4-methoxyphenyl)-3-methylthiochroman-4-yl]octyl}-2-(4,4,5,5,5-pentafluoropentyl)malonate(3.7 g, Yield 71%) as a foamy oil.

¹H-NMR (270 MHz, CDCl₃): δ 7.28 (d, 2H), 6.91 (m, 3H), 6.7 (d, 1H), 6.59(dd, 1H), 3.81 (d, 6H), 3.72 (s, 6H), 3.65 (d, 1H), 2.99 (d, 1H), 2.74(d, 1H), 2.2-1.8 (m, 6H), 1.55-1.0 (m, 19H).

A solution of potassium hydroxide (22.35 g, 398.4 mmol) in water (70 ml)was added to a solution of dimethyl2-{8-[(3S,4S)-7-methoxy-3-(4-methoxyphenyl)-3-methylthiochroman-4-yl]octyl}-2-(4,4,5,5,5-pentafluoropentyl)malonate(7.0 g, 9.96 mmol) in ethanol (140 ml), followed by heating under refluxfor 15 hours. The reaction mixture was adjusted to pH 4 by addition ofhydrochloric acid at 0° C. and then concentrated under reduced pressure.Water was added to the residue, which was then extracted with ethylacetate. The organic layer was washed with water and dried overanhydrous magnesium sulfate. After distilling off the solvent, asolution of boron tribromide in dichloromethane (1N, 59.76 ml, 59.76mmol) was added to a solution of the residue in dichloromethane (100 ml)at −78° C. The resulting mixture was stirred and warmed to 0° C. over 3hours. Water was added to the reaction mixture, which was then extractedwith dichloromethane. The organic layer was washed with saturatedaqueous sodium chloride and dried over anhydrous magnesium sulfate.After distilling off the solvent, toluene (50 ml) was added to theresidue, followed by heating under reflux for 72 hours. Water was addedto the reaction mixture, which was then extracted with ethyl acetate.The organic layer was washed with saturated aqueous sodium chloride anddried over anhydrous magnesium sulfate. After distilling off thesolvent, the residue was purified by silica gel column chromatography(eluent: hexane/ethyl acetate/dichloromethane=5/1/1) to give10-[(3S,4S)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)decanoicacid (3.4 g, Yield 57.8%).

¹H-NMR (270 MHz, CDCl₃): δ 9.20 (s, 1H), 7.22 (d, J=7.92 Hz, 2H), 6.86(d, 1H), 6.73 (d, 2H), 6.52 (s, 1H), 6.42 (d, 1H), 3.5 (d, 1H), 3.01 (d,1H), 2.72 (d, 1H), 2.32-2.06 (m, 3H), 1.6-0.8 (m, 23H), EI-MS: 602 (M+).

Example 4 Synthesis of11-[(3R,4R)-7-Hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)undecanoicAcid

Starting with the(3R,4R)-7-methoxy-3-(4-methoxy-phenyl)-3-methyl-4-(2-propenyl)thiochromanprepared in Example 2 and ethyl2-(4,4,5,5,5-pentafluoropentyl)-9-decenoate separately prepared from1-iodo-4,4,5,5,5-pentafluoropentane, diethyl malonate and1-iodo-7-octene, a procedure analogous to that as shown in Example 2 or3 was repeated to give11-[(3R,4R)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)undecanoicacid.

¹H-NMR (270 MHz, CDCl₃): δ 7.22 (d, 2H), 6.82 (m, 3H), 6.64 (d, 1H),6.52 (dd, 1H), 3.59 (d, 1H), 2.95 (d, 1H), 2.65 (bs, 1H), 2.37 (m, 1H),2.11-1.91 (m, 2H), 1.75-1.43 (m, 6H), 1.32-0.98 (m, 19H).

Example 5 Synthesis of11-[(3S,4S)-7-Hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)undecanoicAcid

Starting with the(3S,4S)-7-methoxy-3-(4-methoxy-phenyl)-3-methyl-4-(2-propenyl)thiochromanprepared in Example 3 and ethyl2-(4,4,5,5,5-pentafluoropentyl)-9-decenoate separately prepared from1-iodo-4,4,5,5,5-pentafluoropentane, diethyl malonate and1-iodo-7-octene, a procedure analogous to that as shown in Example 2 or3 was repeated to give11-[(3S,4S)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)undecanoicacid.

¹H-NMR (270 MHz, DMSO-d6): δ 9.24 (bs, 1H), 7.23 (d, 2H, J=8.3 Hz), 6.85(d, 1H, J=8.24 Hz), 6.73 (d, 2H, J=8.6 Hz), 6.50 (s, 1H), 6.41 (d, 1H,J=7.92 Hz), 3.52 (d, 1H), 3.02 (d, 1H), 2.74 (bs, 1H), 2.30-0.92 (m,29H).

Example 6 Optical Resolution of7-Hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-one

Optical resolution of(±)-7-hydroxy-3-(4-hydroxy-phenyl)-3-methylchroman-4-one was carried outusing a chiral column (CHIRALCEL OD) to give(+)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-one and(−)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-one.

Example 7 Synthesis of11-[7-Hydroxy-3-(4-hydroxyphenyl)-3-methyl-chroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)undecanoicAcid Having Chiral Carbons at Positions 3 and 4

A solution of (+)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-one(2.0 g, 7.40 mmol) in anhydrous tetrahydrofuran (30 ml) was cooled to−78° C. To this solution, a solution of diisobutylaluminum hydride intoluene (1N, 22.94 ml, 22.94 mmol) was slowly added dropwise, and theresulting mixture was stirred for 35 minutes at −78° C. Methanol (1 ml)was added to the reaction mixture at −78° C., which was then warmed to0° C. and further saturated aqueous ammonium chloride (5 ml) andconcentrated hydrochloric acid (7 ml) were added to the mixture followedby stirring for 30 minutes. The reaction mixture was extracted twicewith ethyl acetate. The combined organic layers were washed with waterand saturated aqueous sodium chloride, and then dried over anhydrousmagnesium sulfate. After distilling off the solvent, zinc iodide (2.55g, 7.98 mmol) was added to a suspension of the residue andallyltrimethylsilane (5.3 ml, 33.2 mmol) in 1,2-dichloroethane (80 ml)followed by stirring for 12 hours at room temperature. Saturated aqueousammonium chloride (15 ml), methanol (10 ml) and concentratedhydrochloric acid (10 ml) were added to the reaction mixture, followedby stirring for 30 minutes. The reaction mixture was extracted twicewith dichloromethane. The combined organic layers were washed with waterand saturated aqueous sodium chloride, and then dried over anhydrousmagnesium sulfate. After distilling off the solvent, the residue waspurified by silica gel column chromatography (eluent: ethylacetate/hexane=1/4) to give optically active7-hydroxy-3-(4-hydroxyphenyl)-3-methyl-4-(2-propenyl)chroman(cis-configuration, 859 mg, Yield 44%).

¹H-NMR (270 MHz, CDCl₃): δ 7.10 (d, J=8.6 Hz, 2H, Ar—H), 6.91 (d, J=8.6Hz, 1H, Ar—H), 6.84 (d, J=8.6 Hz, 2H, Ar—H), 6.3-6.4 (m, 2H, Ar—H),6.5-6.7 (m, 1H, vinyl-H), 4.60-5.00 (br, 2H, OH), 4.86 (d, J=10.2 Hz,1H, vinyl-H), 4.69 (d, J=16.8 Hz, 1H, vinyl-H), 4.51 (d, J=10.6 Hz, 1H,C2-H), 4.24 (dd, J=10.6, 2.0 Hz, C2-H), 2.7-2.8 (m, 1H, C4-H), 2.0-2.15(m, 1H, allylic-H), 1.75-1.9 (m, 1H, allylic-H), 1.28 (s, 3H, C3-CH₃).

Starting with the optically active7-hydroxy-3-(4-hydroxyphenyl)-3-methyl-4-(2-propenyl)chroman prepared inStep 1, a procedure analogous to that as shown in Example 4 or 5 wasrepeated without protection of hydroxyl groups to give11-[7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)undecanoicacid with a cis-configuration having chiral carbons at positions 3 and4.

¹H-NMR (270 MHz, CDCl₃): δ 7.08 (d, J=8.6 Hz, 2H, Ar—H), 6.90 (d, J=8.9Hz, 1H, Ar—H), 6.82 (d, J=8.6 Hz, 2H, Ar—H), 6.3-6.4 (m, 2H, Ar—H),4.4-5.6 (bs, 2H, OH), 4.51 (d, J=10.2 Hz, 1H, C2-H), 4.24 (dd, J=10.2,1.3 Hz, 1H, C2-H), 2.55-2.65 (m, 1H, C4-H), 2.35-2.5 (m, 1H, CHCO₂H),1.9-2.2 (m, 2H, CH₂CF₂), 0.95-1.80 (m, 25H, C3-CH₃and alkyl-H).

Example 8 Synthesis of11-[7-Hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)undecanoicAcid Having Chiral Carbons at Positions 3 and 4

Starting with the(−)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-one prepared inExample 6, a procedure analogous to that as shown in Example 7 wasrepeated to give11-[7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)undecanoicacid with a cis-configuration having chiral carbons at positions 3 and4.

¹H-NMR (270 MHz, CDCl₃): δ 7.07 (d, J=9 Hz, 2H, Ar—H), 6.90 (d, J=9 Hz,1H, Ar—H), 6.82 (d, J=9 Hz, 2H, Ar—H), 6.3-6.4 (m, 2H, Ar—H), 4.51 (d,J=10 Hz, 1H, C2-H), 4.23 (d, J=10 Hz, 1H, C2-H), 2.59 (m, 1H, C4-H),2.38 (m, 1H, CHCO₂H), 1.9-2.2 (m, 2H, CH₂CF₂), 0.95-1.80 (m, 25H, C3-CH₃and alkyl-H).

Example 9 Synthesis of Optically Active11-[(3RS,4RS)-7-Hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-yl]-2-(4,4,5,5,5-penta-fluoropentyl)undecanoicAcid Having a Chiral Carbon at α-position to the Carboxyl Group

After 60% sodium hydride (480 mg) was washed twice with anhydroustoluene and suspended in anhydrous toluene, a solution of(1S)-(−)-2,10-camphorsultam (1.72 g) in anhydrous toluene (25 ml) wasadded to the suspension, followed by stirring for 1 hour at roomtemperature. A solution of 9-decenoylchloride (3.02 g) in anhydroustoluene (25 ml) was further added dropwise to the suspension, followedby stirring for 12 hours at room temperature. Water (30 ml) was added tothe reaction mixture, which was then extracted with ethyl acetate. Theorganic layer was washed with water and saturated aqueous sodiumchloride, dried over anhydrous sodium sulfate, and evaporated underreduced pressure to remove the solvent, followed by purification viaflash column chromatography to give acylated product 2 (2.08 g, Yield70%). To a solution of the thus prepared acylated product 2 (368 mg) intetrahydrofuran (2 ml), a solution of NaHMDS in tetrahydrofuran (1M, 1.0ml) was added dropwise over 5 minutes while cooling at −78° C., followedby stirring for 1 hour at the same temperature. The reaction mixture wasfurther mixed with 1-iodo-4,4,5,5,5-pentafluoropentane (432 mg) and HMPA(0.522 ml) and then warmed slowly to room temperature. Saturated aqueouschloride was added to the reaction mixture, which was then extractedwith ethyl acetate. The organic layer was washed with water andsaturated aqueous sodium chloride, dried over anhydrous sodium sulfate,and evaporated under reduced pressure to remove the solvent, followed bypurification via flash column chromatography to give alkylated product 3(297 mg, Yield 56%).

¹H-NMR (270 MHz, CDCl₃): δ 5.7-5.9 (m, 1H, vinyl), 4.9-5.1 (m, 2H,vinyl), 3.91 (t, 1H, J=6.3 Hz), 3.51 (d, 1H, J=13.9 Hz), 3.43 (d, 1H,J=13.9 Hz), 3.0-3.2 (m, 1H), 0.8-2.2 (m, 25H), 1.14 (s, 3H, Me), 0.97(s, 3H, Me).

Starting with the optically active compound 3 prepared in Step 1 (211mg) and(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methyl-4-(2-propenyl)chroman 4(racemate, 59 mg), a procedure analogous to that as shown in Example 7was repeated to effect metathesis, thereby giving a coupling product(125 mg). This coupling product was subjected to hydrogenation as inExample 7 to give a reduction product (87 mg). To a solution of thereduction product (20 mg) in tetrahydrofuran (0.5 ml), 1M aqueouslithium hydroxide (0.15 ml) was added under nitrogen atmosphere,followed by stirring for 1 day at 50° C. The reaction mixture wasacidified by addition of 2N hydrochloric acid, extracted with ethylacetate, dried over anhydrous magnesium sulfate, and evaporated underreduced pressure to remove the solvent, followed by purification viasilica gel column chromatography to give11-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)undecanoicacid 5 having a chiral carbon at α-position to the carboxyl group(7.4mg).

The thus prepared compound 5 was analyzed under the followingconditions. Compound 5 was found to give two peaks at retention times of9.3 and 16.5 minutes, whereas the racemate was found to give four peaksat retention times of 9.3, 10.2, 16.5 and 29.9 minutes.

HPLC analysis conditions: Chiralpak AD (250×4.6 mm ID),hexane/iPrOH/TFA=80/20/0.2, 1.2 ml/min, 206 nm

In addition, the corresponding optically active form of racemate 4 canbe used in this synthesis to prepare a single isomer compound 5.Although this example illustrates the synthesis of a chroman derivative,a thiochroman derivative can also be prepared in an optically activeform by an analogous method.

Example 10

Optical resolution of the10-[(3R,4R)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)decanoicacid prepared in Example 2 was carried out using a chiral column(CHIRALPAK AD) to give optically active isomers, each having chiralcarbons at positions 3 and 4 and at α-position to the carboxyl group.

Each isomer provided the same NMR data as shown in Example 2.

Peaks 1 and 2 were detected at retention times of 10.1 and 13.5 minutes,respectively, under the following conditions:

Column used: CHIRALPAK AD (0.46 cm ID×25 cm L)

Mobile phase: hexane/EtOH/acetic acid=85/15/0.1 (v/v/v)

Flow rate: 1.0 ml/min

Column temperature: 40° C.

Detection wavelength: 254 nm

Example 11

Optical resolution of the10-[(3S,4S)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)decanoicacid prepared in Example 3 was carried out using a chiral column(CHIRALPAK AD) to give optically active isomers, each having chiralcarbons at positions 3 and 4 and at α-position to the carboxyl group.

Each isomer provided the same NMR data as shown in Example 3.

Peaks 1 and 2 were detected at retention times of 9.5 and 10.9 minutes,respectively, under the following conditions:

Column used: CHIRALPAK AD (0.46 cm ID×25 cm L)

Mobile phase: hexane/EtOH/acetic acid=85/15/0.1 (v/v/v)

Flow rate: 1.0 ml/min

Column temperature: 40° C.

Detection wavelength: 254 nm

Test Example 1 Anti-estrogenic Activity (Oral Administration)

Test compounds were assayed for their oral anti-estrogenic activity inthe following manner. In this experiment, the compounds prepared inExamples 2 and 3 were used as test compounds and the correspondingracemic mixture(10-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)decanoicacid was used as a control compound. This control compound wassynthesized according to Reaction Schemes 1 to 7 mentioned above.

To determine anti-estrogenic activity, mice (ICR, weight 30±2 g) whichhad been ovariectomized 2 weeks before were subcutaneously administeredwith 17β-estradiol-benzoate (Sigma) in an amount of 0.1 μg/mouse for 3days and the degree by which the test compound inhibited the increase inuterine weight was measured. In this experiment, each of the test andcontrol compounds was suspended in 5% arabic gum solution and orallyadministered for 3 days on a once-a-day basis. After 24 hours from thelast administration, the test animals were sacrificed and the uteri wereremoved and weighed. The results obtained are shown in Table 2 below.

TABLE 2 Anti-estrogenic activity in ovariectomized mice administeredwith 17β-estradiol (oral administration, 3 days) Test compound/dose(p.o., 3 days) Compound mg/kg Inhibition (%) Example 2 10 90 Example 310 69 Example 10, Peak 1 10 87 Example 10, Peak 2 10 78 10-[(3RS,4RS)-7-hydroxy-3-(4-hydroxy- 10 75 phenyl)-3-methyl-thiochroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)decanoic acid

The results shown in Table 2 above indicate that the compounds of thepresent invention show a superior inhibitory activity against theestradiol-induced increase in uterine weight, as compared to thecorresponding racemic mixture.

INDUSTRIAL APPLICABILITY

The compounds of the present invention are highly advantageous inpharmaceutical use because of their anti-estrogenic activity,particularly their superior anti-estrogenic activity over thecorresponding racemic mixture.

What is claimed is:
 1. A compound having the following general formula(1):

in which x represents an oxygen atom or a sulfur atom, m represents aninteger of 2 to 14, and n represents an integer of 2 to 7, or thefollowing general formula (2):

in which x represents an oxygen atom or a sulfur atom, m represents aninteger of 2 to 14, and n represents an integer of 2 to 7, or thefollowing general formula (3):

in which x represents an oxygen atom or a sulfur atom, m represents aninteger of 2 to 14, and n represents an integer of 2 to 7, or thefollowing general formula (4):

in which x represents an oxygen atom or a sulfur atom, m represents aninteger of 2 to 14, and n represents an integer of 2 to 7, or a hydratethereof.
 2. The compound or hydrate thereof according to claim 1, whichhas general formula (1), (2), (3) or (4) wherein m is an integer of 6 to10.
 3. The compound or hydrate thereof according to claim 1, which hasformula (1), (2), (3) or (4) wherein m is an integer of 8 or
 9. 4. Thecompound or hydrate thereof according to claim 1, which has formula (1),(2), (3) or (4) wherein n is an integer of 3 or
 4. 5. The compound orhydrate thereof according to claim 1, which has general formula (1),(2), (3) or (4) wherein X is an oxygen atom or a sulfur atom, m is aninteger of 8 or 9, and n is an integer of 3 or
 4. 6. The compound orhydrate thereof according to claim 1, which has formula (1) or (2)wherein carbon which is on the side chain bonded to the 4-position ofthe parent scaffold (i.e., chroman or thiochroman ring) and to which thecarboxylic acid in said side chain is bonded has R- or S-configurationor mixtures thereof.
 7. The compound or hydrate thereof according toclaim 1, which has formula (2).
 8. The compound or hydrate thereofaccording to claim 7, wherein X is a sulfur atom.
 9. The compound orhydrate thereof according to claim 1, which has formula (1) or (2)wherein X is an oxygen atom.
 10. The compound or hydrate thereofaccording to claim 1, which is selected from the group consisting of:10-[(3R,4R)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-(2R)-2-(4,4,5,5,5-pentafluoropentyl)decanoicacid;10-[(3R,4R)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-(2S)-2-(4,4,5,5,5-pentafluoropentyl)decanoicacid;10-[(3S,4S)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-(2R)-2-(4,4,5,5,5-pentafluoropentyl)decanoicacid;10-[(3S,4S)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-(2S)-2-(4,4,5,5,5-pentafluoropentyl)decanoicacid;10-[(3R,4R)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)decanoicacid;10-[(3S,4S)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)decanoicacid;10-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-(2R)-2-(4,4,5,5,5-pentafluoropentyl)decanoicacid;10-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-(2S)-2-(4,4,5,5,5-pentafluoropentyl)decanoicacid;11-[(3R,4R)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-(2R)-2-(4,4,5,5,5-pentafluoropentyl)undecanoicacid;11-[(3R,4R)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-(2S)-2-(4,4,5,5,5-pentafluoropentyl)undecanoicacid;11-[(3S,4S)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-(2R)-2-(4,4,5,5,,5-pentafluoropentyl)undecanoicacid;11-[(3S,4S)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-(2S)-2-(4,4,5,5,5-pentafluoropentyl)undecanoicacid;11-[(3R,4R)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)undecanoicacid;11-[(3S,4S)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)undecanoicacid;11-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-(2R)-2-(4,4,5,5,5-pentafluoropentyl)undecanoicacid; and11-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-(2S)-2-(4,4,5,5,5-pentafluoropentyl)undecanoicacid.
 11. A pharmaceutical composition comprising at least one compoundor hydrate thereof according to claim 1 as an active ingredient.
 12. Ananti-estrogenic pharmaceutical composition comprising at least onecompound or hydrate thereof according to claim 1 as an activeingredient.
 13. A therapeutic agent for breast cancer comprising atleast one compound or hydrate thereof according to claim 1 as an activeingredient.